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Summary: Chronic kidney disease (CKD) increases fracture risk. The results of this work point to changes in bone collagen and bone hydration as playing a role in bone fragility associated with CKD. Introduction: Clinical data have documented a clear increase in fracture risk associated with chronic kidney disease (CKD). Preclinical studies have shown reductions in bone mechanical properties although the tissue-level mechanisms for these differences remain unclear. The goal of this study was to assess collagen cross-links and matrix hydration, two variables known to affect mechanical properties, in animals with either high- or low-turnover CKD. Methods: At 35 weeks of age (>75 % reduction in kidney function), the femoral diaphysis of male Cy/+ rats with high or low bone turnover rates, along with normal littermate (NL) controls, were assessed for collagen cross-links (pyridinoline (Pyd), deoxypyridinoline (Dpd), and pentosidine (PE)) using a high-performance liquid chromatography (HPLC) assay as well as pore and bound water per volume (pw and bw) using a H nuclear magnetic resonance (NMR) technique. Material-level biomechanical properties were calculated based on previously published whole bone mechanical tests. Results: Cortical bone from animals with high-turnover disease had lower Pyd and Dpd cross-link levels (−21 % each), lower bw (−10 %), higher PE (+71 %), and higher pw (+46 %) compared to NL. Animals with low turnover had higher Dpd, PE (+71 %), and bw (+7 %) along with lower pw (−60 %) compared to NL. Both high- and low-turnover animals had reduced material-level bone toughness compared to NL animals as determined by three-point bending. Conclusions: These data document an increase in skeletal PE with advanced CKD that is independent of bone turnover rate and inversely related to decline in kidney function. Although hydration changes occur in both high- and low-turnover disease, the data suggest that nonenzymatic collagen cross-links may be a key factor in compromised mechanical properties of CKD. [ABSTRACT FROM AUTHOR]